Lu and Wang Cancer Commun (2018) 38:63 https://doi.org/10.1186/s40880-018-0336-6 Cancer Communications

REVIEW Open Access Nonmetabolic functions of metabolic enzymes in cancer development Sean Lu and Yugang Wang*

Abstract Metabolism is a fundamental biological process composed of a series of reactions catalyzed by metabolic enzymes. Emerging evidence demonstrates that the aberrant signaling in cancer cells induces nonmetabolic functions of meta- bolic enzymes in many instrumental cellular activities, which involve metabolic enzyme-mediated protein post-trans- lational modifcations, such as phosphorylation, acetylation, and succinylation. In the most well-researched literatures, metabolic enzymes phosphorylate proteins rather than their metabolites as substrates. Some metabolic enzymes have altered subcellular localization, which allows their metabolic products to directly participate in nonmetabolic activities. This review discusses how these fndings have deepened our understanding on enzymes originally classi- fed as metabolic enzymes, by highlighting the nonmetabolic functions of several metabolic enzymes responsible for the development of cancer, and evaluates the potential for targeting these functions in cancer treatment. Keywords: Metabolic enzymes, Function, Protein kinase, Metabolite products, Phosphorylation, Acetylation, Succinylation, Mitochondria

Introduction reactions in which they were originally characterized to Metabolism, regulated by metabolic enzymes, supports work on. For instance, several metabolic enzymes use cell growth and proliferation by providing energy for cel- proteins as substrates and function as protein kinases lular activities and synthesizing the molecular building to phosphorylate these protein substrates, thereby regu- blocks for production of amino acids, nucleotides, and lating diverse functions [1]. Second, metabolic enzymes lipids. Metabolic enzymes are responsible for specifc that translocate from their original subcellular compart- chemical reactions on metabolites, which takes place ments to diferent organelles, where their metabolite under strict regulation at specifc subcellular locations products are directly used for protein modifcations or in the metabolic cascades. Metabolic enzymes, such as acting as instrumental regulators for other proteins. For carboxylases, dehydrogenases, lipoxygenases, oxidore- instance, mitochondrial α-ketoglutarate dehydrogenase ductases, kinases, lyses, and transferases carry out a wide (α-KGDH) that translocates to the nucleus and produces range of catalytic activities and are responsible for a vari- succinyl-coenzyme A (CoA), which is used by the histone ety of cellular functions necessary for cellular homeosta- acetyltransferase, lysine acetyltransferase 2A (KAT2A), to sis and survival. succinylate histone H3 [2, 3]. In addition, mitochondrial Recent literatures have determined that some meta- fumarase, when translocated to the nucleus, produces bolic enzymes possess nonmetabolic activities that are fumarate that inhibits lysine demethylase 2B (KDM2B) critical in the development of cancer. Tese nonmetabolic histone demethylase activity and enhances the methyla- activities can be divided into two categories. First, meta- tion of histone H3 and the repair of damaged DNA [4]. bolic enzymes that use non-metabolites as substrates to Tis review summarizes the recent fndings regarding catalyze reactions that are distinct from the metabolic these nonmetabolic functions of metabolic enzymes and highlights the implication of these functions in cancer development. *Correspondence: [email protected] Brain Tumor Center and Department of Neuro‑Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

© The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat​iveco​mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat​iveco​mmons​.org/ publi​cdoma​in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Lu and Wang Cancer Commun (2018) 38:63 Page 2 of 7

Metabolic enzymes function as protein kinases of the cytokinesis process, and proliferation of tumor Protein kinases are critical regulators of intracellular cells [16]. In addition, it has been found that in hepato- signal transduction pathways that mediate various cel- cellular carcinoma (HCC), PKM2 phosphorylates the lular processes in both unicellular and multicellular sterol regulatory element-binding proteins (SREBPs) at organisms. Tey can directly transfer the γ-phosphate Tr59, activates lipid biosynthesis, and promotes the pro- from adenosine triphosphate (ATP) to specifc tyros- liferation of the cancer cells [17]. Apart from its functions ine (Tyr), serine (Ser), threonine (Tr), and histidine in regulating gene expression and cell cycle progression, (His) residues on substrate proteins, thereby altering PKM2 has been demonstrated to phosphorylate serine/ the functions of these substrates. More than 500 protein threonine kinase 1 (AKT1) at Ser202/203 to release it kinases have been identifed in humans, constituting of from the regulatory-associated protein of mTOR (rap- about 1.7% of all human genes [5]. Recent studies have tor), which subsequently promotes hormonal and nutri- demonstrated that several metabolic enzymes, such as ent signaling-independent activation of the mammalian pyruvate kinase M2 (PKM2), phosphoglycerate kinase 1 target of rapamycin complex 1 (mTORC1), to provide (PGK1), ketohexokinase-A (KHK-A), hexokinases (HK), survival and proliferation advantages over normal cell nucleoside diphosphate kinase (NDPK or NDK), and upon stimulus by the epidermal growth factor receptor 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (EGFR)-dependent activation of nuclear factor kappa (PFKFB4), have unexpected protein kinase activities and enhancer binding protein (NF-κB) [6, 18]. play signifcant roles in nonmetabolic cellular functions. In response to oxidative stress, PKM2 promotes cell Tese new studies expand the family of protein kinases survival by translocating into the mitochondria, phos- and provide new insights into the integrated regulation of phorylating the apoptosis regulator Bcl2 at Tr69 to sta- cell metabolism and other cellular processes. bilize Bcl2, which blocks its association with Cul3-based E3 ligase to prevent the degradation of Bcl2 and pro- PKM2 motes the resistance of tumor cells against apoptosis [19]. Pyruvate kinase (PK) catalyzes the fnal rate-limiting step Further, as PKM2 can also phosphorylate the synapto- of glycolysis and converts phosphoenolpyruvate (PEP) to some-associated protein 23 (SNAP23) at Ser95, resulting pyruvate by transferring a phosphate group from PEP to in the formation of the soluble N-ethylmaleimide sensi- adenosine diphosphate (ADP), producing ATP. It has four tive factor attachment protein receptors (SNARE) com- isoforms: PKL, PKR, PKM1, and PKM2. PKM2 is highly plex, this demonstrates that PKM2 has contribution in expressed in cancer cells [6]. Besides, although PKM1 has the remodeling of the tumor microenvironments by pro- a higher glycolytic activity than PKM2, only the protein moting tumor cell exosome secretions, which are neces- kinase activity of PKM2 has been described till present. sary for the docking of tumor cells to plasma membranes PKM2 is involved in the regulation of gene expression, [20]. A recent report has shown that in pancreatic ductal mitosis, apoptosis, and other critical cellular activities adenocarcinoma, PKM2 could phosphorylate the ser- that promote aerobic glycolysis and tumor growth [7–9]. ine/threonine protein kinase PAK2 at Ser20, Ser141, and PKM2’s protein kinase activity was initially identifed Ser 192/197 to recruit heat shock protein 90 for increas- from the phosphorylation of histone H3 at Tr11 and ing the stability of the PAK2 protein, thereby promoting that of signal transducer and activator of transcription invasion and metastasis of the pancreatic cancerous cells 3 (STAT3) at Tyr705. In the nucleus, PKM2-mediated [21]. Further, PKM2 was observed to promote genomic histone H3 phosphorylation promotes β-catenin- and instability, an important hallmark of cancer develop- c-Myc-mediated gene expression, which enhances aero- ment and progression due to increased interruption of bic glycolysis and promotes the proliferation of tumor DNA repair, in breast cancer cells breast cancer since cells [10–14]. During mitosis, PKM2 binds to the spindle it was demonstrated that nuclear PKM2 could interact checkpoint protein Bub3 and phosphorylate it at Tyr207 with and directly phosphorylate histone H2AX at Ser139 to enable the interaction of the Bub3–Bub1 complex with under DNA damaged conditions to induce chromosomal kinetochores, which is essential for the mitotic/spindle- aberrations and promote cancer cell proliferation [22]. assembly checkpoint, accurate chromosome segregation, Furthermore, phosphoproteomic studies in yeast and and tumorigenesis [15]. PKM2 also phosphorylates myo- mammalian cells have revealed that hundreds of addi- sin light chain 2 (MLC2) at Tyr118, primes the binding tional proteins, including many protein kinases such as of Rho-associated protein kinase 2 (ROCK2) to MLC2 extracellular signal-regulated kinase (ERK), AKT1 sub- and the phosphorylation of ROCK2–MLC2 complex at strate 1 (AKT1S1), BLK, can be phosphorylated by PKM2 Ser15, to allow the interaction between myosin II with [18, 23, 24], suggesting that PKM2’s protein kinase activi- actin, which is required for the contractile function of the ties have instrumental roles in a wide array of cellular actomyosin complex at the cleavage furrow, completion functions. Lu and Wang Cancer Commun (2018) 38:63 Page 3 of 7

PGK1 of fructose, slows the fructose catabolism rates, ATP PGK1 is an enzyme responsible for the frst ATP-gen- consumption, and reactive oxygen species production in erating step in the glycolysis pathway and is highly HCC cells [30]. Importantly, instead of binding to fruc- expressed in many types of cancer [25]. It catalyzes the tose, KHK-A interacts with the rate-limiting enzyme reversible conversion of 1,3-diphosphoglycerate and phosphoribosyl pyrophosphate synthetase 1 (PRPS1) ADP to 3-phosphoglycerate and ATP, respectively [25]. in the de novo nucleic acid synthesis pathway and acts And similar to PKM2, PGK1 also has protein kinase as a protein kinase to directly phosphorylate PRPS1 at activity to phosphorylate protein substrates. We found Tr225. Tis phosphorylation blocks the ADP binding- that mitochondria-translocated PGK1 uses ATP as a mediated inhibition of PRPS1, resulting in elevated de phosphate donor to directly phosphorylate and activate novo nucleic acid synthesis via the constitutive activa- pyruvate dehydrogenase kinase isozyme 1 (PDHK1) tion of PRPS1 and enhancing HCC cell proliferation at Tr338. Te subsequent PDHK1-mediated phos- and liver tumor growth in mice. KHK-A expression and phorylation of pyruvate dehydrogenase E1α at Ser293 PRPS1 Tr225 phosphorylation levels are positively cor- inhibits the pyruvate dehydrogenase complex (PDC) related with each other in human HCC specimens and and the conversion of pyruvate and CoA to acetyl-CoA are inversely correlated with survival in HCC patients, in the mitochondria, which suppresses the mitochon- indicating that KHK-A-dependent PRPS1 phosphoryla- drial pyruvate oxidation and increases lactate production tion is pivotal in HCC progression [28, 30]. from pyruvate in the cytosol. Tus, mitochondrial pyru- vate metabolism suppressed by PGK1 couples with the HK upregulation of glycolytic gene expression mediated by Most cancers ensure sufcient energy supplies via gly- nuclear PKM2 to promote the Warburg efect and tumo- colysis which are the basis for their growth and prolif- rigenesis [26]. In addition, the protein kinase activity of eration. However, the systemic inhibition of glycolysis PGK1 is involved in the initiation of autophagy, impor- as an anti-cancer approach would result in considera- tant for homogenizing cell homeostasis. When tumors ble adverse efects since normal cells also supplements start outgrowing existing vasculature, this result in glu- themselves with energy through glycolysis. Terefore, tamine deprivation and hypoxia within the tumor cells the selective inhibition of cancer-driven glycolysis has and ARD1 acetyl-transferase acetylates PGK1 at Lys388, been investigated for clinical cancer therapy and HK which in turn phosphorylates Beclin1 at Ser30, leading was proposed as a therapeutic target. HK enzymes have to a conformational change and activation of class III been found to be essential in the frst step of the glu- phosphatidylinositol (PI) 3-kinase (VPS34) to produce cose metabolism pathway as they catalyse the phospho- phosphatidylinositol 3-phosphate (PI(3)P), facilitating rylation of glucose to produce glucose 6-phosphate by the initiation of tumor-autophagy and promotes tumor using ATP as the phosphate donor. Phosphoamino acid development [27]. Tus, targeting PGK1 can be an attrac- analyses revealed that HK1 purifed from rat brains can tive therapeutic approach for cancer treatment. be autophosphorylated at serine, threonine, and tyrosine residues [31], and in vitro phosphorylation assays showed that HK1 can phosphorylate itself and purifed histone KHK‑A H2A [32]. However, the diferent isoforms of HK need to KHK, also known as fructokinase, is responsible for the be characterized and whether HK1 or other HK isoforms frst rate-limiting enzymatic reaction in fructose metab- act as protein kinases in vivo remains unclear, as does the olism. KHK catalyzes the transfer of a phosphate group physiological role of any such phosphorylation activity in from ATP to fructose, producing fructose 1-phosphate the regulation of cellular activities associated with cancer (F1P) and ADP. Aldolase then catalyzes the F1P into development. dihydroxyacetone phosphate and glyceraldehyde, which are subsequently converged into the glycolysis pathway NDPK1/2 [28]. Among the alternatively spliced isoforms of the NDPK is a ubiquitous enzyme in mammals. It catalyzes precursor ribonucleic acid (RNA) of KHK, highly active the conversion of nucleoside diphosphates (NDPs) into KHK-C, but not inactive KHK-A, is highly expressed in nucleoside triphosphates (NTPs) by transferring the the liver, kidneys, and pancreas [29]. In HCC cells, c-Myc γ-phosphate group from the 5′-triphosphate nucleotides induces the expression of heterogeneous nuclear ribo- to the 5′-diphosphate nucleotides [33]. In this process, nuclear proteins H1 (HnRNPH1) and nRNPH2, which NDPK uses an NTP (usually ATP) and autophosphorylate regulates the splicing of the KHK precursor mRNA and itself at a highly conserved histidine residue in its active switches KHK-C to KHK-A. Te expression of KHK-A, site. Te phosphate group is then transferred from the which has a much lower activity toward phosphorylation phosphohistidine to an NDP molecule or to a histidine Lu and Wang Cancer Commun (2018) 38:63 Page 4 of 7

on the substrate protein [34]. Several proteins have been ACSS2 identifed as substrates of NDPK-A and NDPK-B protein Histone acetylation requires nuclear acetyl-CoA and is kinase activity. For instance, NDPK-A phosphorylates the critical for gene expression. ACSS2 is a non-mitochon- histidine at the catalytic site of ATP citrate lyase (ACLY) drial source of acetyl-CoA, which localizes in the cyto- and regulates ACLY-dependent acetyl-CoA production sol and the nucleus, and catalyzes the ligation of acetate, for fatty acid synthesis [35]. NDPK-B can form a complex both from exogenous sources and recycled histone dea- with G protein βγ dimers and phosphorylate the Gβ sub- cetylase reactions, to CoA to produce acetyl-CoA [42, unit at His266. Te phosphate group is then transferred 43]. In response to stresses such as hypoxia the amount to guanosine diphosphate (GDP), leading to the forma- of nutrients becomes limited, conditions commonly tion of guanosine triphosphate (GTP) and the activa- observed in tumor microenvironments, and cytosolic tion of G protein [36]. NDPK-B also phosphorylates the ACSS2 is translocated to the nucleus, where it forms a Ca­ 2+-activated ­K+ channel KCa3.1 at His358. Tis phos- complex with transcription factor EB (TFEB), locally pro- phorylation relieves the copper-dependent inhibition ducing acetyl-CoA for histone H3 acetylation in the pro- of KCa3.1 channel function and promotes subsequent moter regions of TFEB-regulated autophagosomal and activation of ­CD4+ T cells [37, 38]. In addition, NDPK-B lysosomal genes. Te expression of these genes promotes phosphorylates the C-terminal tail of transient receptor glucose deprivation-induced autophagy and lysosomal potential vanilloid 5 at His711 and regulates urinary ­Ca2+ biogenesis, tumor cell survival, and proliferation [43]. excretion by mediating active Ca­ 2+ reabsorption in the distal convoluted tubule of the kidney [39]. However, like ACLY that of HK, the role of the protein histidine-kinase activ- ACLY, which catalyzes the conversion of oxidation- ity of NDPK in the development of cancer are yet to be derived mitochondrial citrate into acetyl-CoA and uncovered. oxaloacetate, provides an important source of cytosolic acetyl-CoA. Nevertheless, ACLY is also found in the PFKFB4 nucleus, and the spatial and temporal control of nuclear In humans, four genes encode phosphofructokinase two ACLY-dependent acetyl-CoA production plays an impor- proteins: PFKFB1, PFKFB2, PFKFB3, and PFKFB4. Tese tant role in histone acetylation and regulation of gene proteins vary dramatically in their tissue expression, reg- expression [44–46]. Te identifcation of co-regulators ulation, and kinase-to-phosphatase activity. Phosphof- that are in complex with ACLY will shed further light on ructokinase 2 promotes glycolysis by phosphorylation to the selective regulation of gene expression. generate fructose 6-phosphate, an allosteric activator of phosphofructokinase 1. In a recent study, PFKFB4 was PDC found to have protein kinase activity that phosphoryl- In addition to ACLY and ACSS2, PDC, which is primar- ates steroid receptor coactivator-3 (SRC3) at the Ser857 ily located in the mitochondria, is another non-mito- [40], which promotes the association of SRC3 with the chondrial source of acetyl-CoA. Upon treatment of cells activating transcription factor 4 (ATF4) to induce gene with serum and epidermal growth factor, PDC trans- expression of the enzymes transketolase, adenosine locates into the nucleus and generates acetyl-CoA for monophosphate deaminase-1 (AMPD1), and xanthine histone acetylation [47]. As with ACLY, the complexed dehydrogenase (XDH), involved in the purine metabo- proteins with PDC that control gene expression remain lism to promote metastasis. As such, PFKFB4-activated undetermined. SRC3 activation drives glucose fux towards the pentose phosphate pathway, enhances purine synthesis, and pro- α‑KGDH motes tumor progression [41]. Mitochondrial α-KGDH catalyzes the conversion of α-ketoglutarate into succinyl-CoA in the tricarbox- Metabolic enzymes regulate cellular activity ylic acid cycle. In our recent studies, we have demon- via their metabolite products strated that a small percentage of α-KGDH is located Metabolic enzymes can form complexes with other pro- in the nucleus [2]. Nuclear α-KGDH interacts with teins and regulate the functions of these proteins via KAT2A to form a high-order assembly and locally con- their metabolite products. Our research group and oth- verts α-ketoglutarate and CoA into succinyl-CoA, which ers have demonstrated that nucleus-localized acetyl-CoA can be used by KAT2A to succinylate histone H3 [2, 3]. synthetase short-chain family member 2 (ACSS2), ACLY, Nuclear α-KGDH-coupled KAT2A functions as a histone PDC, α-KGDH, and fumarase are in complex with chro- succinyltransferase to regulate gene expression, which is matin modulators and regulate gene expression and DNA pivotal in promoting cancer cell proliferation and tumor repair through their metabolite products. growth [2, 3]. Lu and Wang Cancer Commun (2018) 38:63 Page 5 of 7

Fumarase to the development of new and specifc therapeutics for Fumarase catalyzes the reversible reaction of fumarate improving cancer treatments. to malate in the mitochondria and cytosol. Upon induc- tion of DNA damage by ionizing radiation, fumarase Abbreviations translocates from the cytosol into the nucleus. In the α-KGDH: α-ketoglutarate dehydrogenase; ACLY: ATP-citrate lyase; ACSS2: nucleus, DNA-dependent protein kinase (DNA-PK)- acetyl-CoA synthetase short chain family member 2; ATF4: cyclic AMP- dependent transcription factor; CoA: coenzyme A; DNA-PK: DNA-dependent phosphorylated fumarase binds to histone H2A.Z at irra- protein kinase; F1P: fructose 1-phosphate; HCC: hepatocellular carcinoma; HK: diation-induced double-strand break regions and locally hexokinase; KAT2A: histone acetyltransferase KAT2A; KDM2B: lysine-specifc produces fumarate, which inhibits α-ketoglutarate- demethylase 2B; KHK: ketohexokinase; MLC2: myosin light chain 2; NDP: nucle- oside diphosphate; NDPK: nucleoside diphosphate kinase; NTP: nucleoside dependent KDM2B activity. Tus, H2A.Z-complexed triphosphate; PDC: pyruvate dehydrogenase complex; PDHK1: pyruvate dehy- fumarase increases the demethylation of histone H3K36 drogenase kinase isozyme 1; PEP: phosphoenolpyruvate; PFKFB: 6-phosphof- and accumulation of the DNA-PK complex at DNA dam- ructo-2-kinase/fructose-2,6-biphosphatase; PGK1: phosphoglycerate kinase 1; PKM2: pyruvate kinase M2; PRPS1: phosphoribosyl pyrophosphate synthetase age foci to induce nonhomologous end joining DNA 1; SRC3: steroid receptor coactivator 3; TFEB: transcription factor EB. repair and enhance cell survival. In addition, chromatin- associated fumarase can regulate gene transcription. Authors’ contributions SL and YW wrote and revised this article. Both authors read and approved the Under conditions of glucose deprivation, AMP-activated fnal manuscript. protein kinase-phosphorylated fumarase binds to the transcription factor ATF2 and translocates to ATF2-reg- Acknowledgements ulated gene promoter regions, where fumarase-catalyzed We thank Amy Ninetto at the Department of Scientifc Publications at MD fumarate inhibits KDM2A, increases histone H3K36 Anderson Cancer Center for the critical proof-reading of this manuscript. demethylation and gene expression to inhibit cell growth. Competing interests Tus, the role of fumarase in DNA damage repair and The authors declare that they have no competing interests. regulation of gene expression depends on its post-trans- lational modifcations and interacting proteins. Availability of data and materials Not applicable.

Consent for publication Conclusions and perspective Not applicable.

Recent studies have demonstrated that metabolic Ethics approval and consent to participate enzymes have nonmetabolic activity. Te characteriza- Not applicable. tion of this activity has expanded our understanding Funding on the integrated spatial and temporal control of meta- This work was supported by the 2018 UT Proteomics Network Pilot Fund (to bolic and nonmetabolic processes [48, 49]. Te charac- Y.W.), and the NIH/NCI Cancer Center Support Grant P30CA016672 and Brain terization of multiple types of protein kinase activities Cancer SPORE 2P50 CA127001. of PKM2, PGK1, KHK-A, HK, PFKFB4, and NDPK-A/B Received: 6 September 2018 Accepted: 21 October 2018 makes the identifcation of the protein kinase activity of other metabolic enzymes a reasonable quest. Te ability of these metabolic enzymes to transfer their phosphate groups to substrate proteins instead of that of their sub- References strate metabolites indicates the non-ridged substrate 1. Lu ZM, Hunter T. Metabolic kinases moonlighting as protein kinases. Trends Biochem Sci. 2018;43(4):301–10. https​://doi.org/10.1016/j. selectivity in the chemical reactions that are catalyzed by tibs.2018.01.006. metabolic enzymes. 2. Wang YG, Guo YR, Liu K, Yin Z, Liu R, Xia Y, et al. KAT2A coupled with the In addition to these alternative enzymatic activities, alpha-KGDH complex acts as a histone H3 succinyltransferase. Nature. 2017;552(7684):273. https​://doi.org/10.1038/natur​e2500​3. altered subcellular localization also contributes to the 3. Wang Y, Guo YR, Xing D, Tao YJ, Lu Z. Supramolecular assembly of KAT2A involvement of metabolic enzymes in nonmetabolic pro- with succinyl-CoA for histone succinylation. Cell Discov. 2018. https​://doi. cesses [48, 50]. Metabolic reactions takes place in specifc org/10.1038/s4142​1-018-0048-8. 4. Jiang Y, Qian X, Shen J, Wang Y, Li X, Liu R, et al. Local generation of fuma- subcellular compartments to ensure that the metabolites rate promotes DNA repair through inhibition of histone H3 demethyla- enter into the correct metabolic cascade. Most metabolic tion. Nat Cell Biol. 2015;17(9):1158–68. https​://doi.org/10.1038/ncb32​09. enzyme-mediated nonmetabolic reactions occur outside 5. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science. the locations of the originally identifed metabolic reac- 2002;298(5600):1912–34. https​://doi.org/10.1126/scien​ce.10757​62. tions. Importantly, the nonmetabolic functions of meta- 6. Yang W, Xia Y, Cao Y, Zheng Y, Bu W, Zhang L, et al. EGFR-induced and bolic enzymes are crucial to tumorigenesis and cancer PKCepsilon monoubiquitylation-dependent NF-kappaB activation upregulates PKM2 expression and promotes tumorigenesis. Mol Cell. progression. Advances in our understanding of the non- 2012;48(5):771–84. https​://doi.org/10.1016/j.molce​l.2012.09.028. metabolic activities of metabolic enzymes would lead Lu and Wang Cancer Commun (2018) 38:63 Page 6 of 7

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